A variety of systems for identifying and classifying lymphomas have been proposed over the last 25 years. In the 1980's, the Working Formulation was introduced as a method of classifying lymphomas based on morphological and clinical characteristics. In the 1990's, the Revised European-American Lymphoma (REAL) system was introduced in an attempt to take into account immunophenotypic and genetic characteristics in classifying lymphomas (Harris 1994). The most recent standard, set forth by the World Health Organization (WHO), attempts to build on these previous systems (see, Swerdlow et al., eds., WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th ed., International Agency for Research on Cancer; World Health Organization (2008); and Jaffe, E. S., Pathology & Genetics: Tumours of Haematopoietic and Lymphoid Tissues, WHO Classification of Tumours, Pathology and Genetics series (2001)). The WHO classification of lymphomas is based on several factors, including tumor morphology, immunophenotype, recurrent genetic abnormalities, and clinical features.
Other diagnoses that have not been given WHO diagnostic numbers include HIV-associated lymphoma, germinal center B cell-like subtype of diffuse large B cell lymphoma, activated B cell-like subtype of diffuse large B-cell lymphoma, follicular hyperplasia (non-malignant), and infectious mononucleosis (non-malignant).
Although the WHO classification has proven useful in patient management and treatment, patients assigned to the same WHO diagnostic category often have noticeably different clinical outcomes. In many cases, these different outcomes appear to be due to molecular differences between tumors that cannot be readily observed by analyzing tumor morphology.
Diffuse large B cell lymphoma (DLBCL) can be classified as the germinal center B cell (GCB) subtype or the activated B cell (ABC) subtype based on the cell-of-origin (COO) distinction as molecularly described previously by the Lymphoma/Leukemia Molecular Profiling Project (LLMPP) (see Alizadeh et al., Nature, 403: 503-511 (2000)). However, more accurate diagnostic assays are needed to qualify patients for clinical trials using targeted agents and to use as a predictive biomarker.
Therefore, more precise methods are needed for identifying and classifying lymphomas based on their molecular characteristics. The invention provides such methods.